Modulation of Bax and mTOR for Cancer Therapeutics.

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistanc

Anti-HIV-1 Activity of a New Scorpion Venom Peptide Derivative Kn2-7

For over 30 years, HIV/AIDS has wreaked havoc in the world. In the absence of an effective vaccine for HIV, development of new anti-HIV agents is urgently needed. We previously identified the antiviral activities of the scorpion-venom-peptide-derived mucroporin-M1 for three RNA viruses (measles viruses, SARS-CoV, and H5N1). In this investigation, a panel of scorpion venom peptides and their derivatives were designed and chosen for assessment of their anti-HIV activities. A new scorpion venom peptide derivative Kn2-7 was identified as the most potent anti-HIV-1 peptide by screening assays with an EC50 value of 2.76 µg/ml (1.65 µM) and showed low cytotoxicity to host cells with a selective index (SI) of 13.93. Kn2-7 could inhibit all members of a standard reference panel of HIV-1 subtype B pseudotyped virus (PV) with CCR5-tropic and CXCR4-tropic NL4-3 PV strain. Furthermore, it also inhibited a CXCR4-tropic replication-competent strain of HIV-1 subtype B virus. Binding assay of Kn2-7 to HIV-1 PV by Octet Red system suggested the anti-HIV-1 activity was correlated with a direct interaction between Kn2-7 and HIV-1 envelope. These results demonstrated that peptide Kn2-7 could inhibit HIV-1 by direct interaction with viral particle and may become a promising candidate compound for further development of microbicide against HIV-1

Additional file 1: of Bcl2 inhibition of mitochondrial DNA repair

Supplemental data. Supplemental Figures (Figures S1-S4.) are included. (PDF 403 kb

Recycle and recovery of rhodium complexes with water-soluble and amphiphilic phosphines in ionic liquids for hydroformylation of 1-hexene

A biphasic catalysis system composed of ionic liquid and rhodium complexes with water-soluble or amphiphilic phosphine ligands bearing water-soluble groups of sodium sulfonate have been employed for hydroformylation of 1-hexene. The experimental results show that the activity is almost independent of the hydrotropicity of the phosphine ligands in BMI center dot BF4. In this system, the extraction of phosphine species by the organics from the IL phase was quite low but larger than that of rhodium species and showed rather good stability of catalytic activity. A slight decrease in the aldehyde n/i ratio during the catalyst reuse could be recovered, in part, by replenishing certain amount of ligand into the used catalyst system

Evaluation of a combination “lymphocyte apoptosis model” to predict survival of sepsis patients in an intensive care unit

Abstract Background A major challenge in sepsis intervention is unclear risk stratification. We postulated that a panel of biomarkers of lymphocyte apoptosis and immune function, termed the “lymphocyte apoptosis model,” would be an effective tool for predicting 28-day survival for sepsis patients. Methods A total of 52 consecutive sepsis patients were enrolled. Peripheral blood samples were collected on day 1 of admission for quantification of biomarkers of lymphocyte apoptosis and immune function, including lymphocyte count, lymphocyte apoptotic percentage, expression on monocyte HLA-DR, CD4+/CD8+ T cell ratio, T helper type 1 to type 2 ratio (Th1/Th2), cytochrome c levels, and various proinflammatory cytokine levels. Sepsis severity was classified using Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores. Survival was assessed at 28 days. Results Compared with survivors, non-survivors had significantly higher lymphocyte apoptotic percentages and plasma cytochrome c levels and significantly lower lymphocyte counts, Th1/Th2 ratios, and HLA-DR expression on day 1 of admission. Multivariate analysis identified cytochrome c levels (odds ratio [OR]1.829, p = 0.025), lymphocyte apoptotic percentage (OR 1.103, p = 0.028), lymphocyte count (OR 0.150, p = 0.047), and HLA-DR expression (OR 0.923, p = 0.021) as independent predictors of 28-day mortality. A logistic regression equation incorporating the independent risk factors predicted 28-day mortality with greater accuracy than did the APACHE II score or single components biomarkers. Conclusions The “lymphocyte apoptosis model” may be useful for risk stratification and predicting prognosis of sepsis patients

A Benchmark for Accurate GPCR Ligand Binding Affinity Prediction with Free Energy Perturbation

G protein-coupled receptors (GPCRs) are among the most important drug targets in the pharmaceutical industry. Free energy perturbation (FEP), which can accurately predict the relative binding free energies of drug molecules, is now widely used in drug discovery. With the development of structural biology tools such as cryoelectron-microscopy (cryo-EM), the structures of a large number of GPCRs have been resolved, which provides the basis for FEP calculations. In this study, we developed an FEP protocol for GPCR FEP calculation. We performed calculations on 226 perturbation pairs of 139 ligands against 8 GPCRs, spanning 12 datasets (A2A , mGlu5 , D3, OX2 , CXCR4, β1, δ and TA1 receptors) and obtained promising results, particularly for agonist ligands in the TA1 datasets (R2, 0.58, RMSE, 1.07 kcal · mol−1 ). The average R2 is 0.61 and the average RMSE is 0.94 kcal · mol−1 , which is comparable to experimental accuracy(<1 kcal · mol−1 ). We also investigated factors that impact the accuracy of FEP results, including ligand binding pose, water placement, and protein structure. Our input structures for FEP calculation are publicly available as a benchmark dataset for future GPCR-FEP studies (https://doi.org/10.5281/zenodo.7988248). This represents the largest collection of GPCR FEP calculations known to us thus far. This work is expected to significantly contribute to the advancement of GPCR-targeted drug discovery

Increase in Cd Tolerance through Seed-Borne Endophytic Fungus Epichlo&euml; gansuensis Affected Root Exudates and Rhizosphere Bacterial Community of Achnatherum inebrians

Soil cadmium (Cd) pollution is a serious environmental problem imperiling food safety and human health. The endophyte Epichlo&euml; gansuensis can improve the tolerance of Achnatherum inebrians to Cd stress. However, it is still unknown whether and how the endophyte helps host plants build up a specific bacterial community when challenged by CdCl2. In this study, the responses of the structure and function of bacterial community and root exudates of E+ (E. gansuensis infected) and E&minus; (E. gansuensis uninfected) plants to Cd stress were investigated. Analysis of bacterial community structure indicated that the rhizosphere bacterial community predominated over the root endosphere bacterial community in enhancing the resistance of CdCl2 in a host mediated by E. gansuensis. E+ plant strengthened the interspecific cooperation of rhizosphere bacterial species. Moreover, the analysis of root exudates demonstrated E. gansuensis and increased the contents of organic acids and amino acids under Cd stress, and most root exudates were significantly correlated with rhizosphere bacteria. These results suggested that E. gansuensis employed a specific strategy to recruit distinct rhizosphere bacterial species and relevant functions by affecting root exudates to improve the tolerance of the host to Cd stress. This study provides a firm foundation for the potential application of symbionts in improving phytostabilization efficiency